Biliverdin inhibits activation of NF-κB:: Reversal of inhibition by human biliverdin reductase
Biliverdin inhibits activation of NF-κB:: Reversal of inhibition by human biliverdin reductase
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DOI：
10.1002/ijc.22978
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发表时间：
2007-12-01
影响因子：
6.4
通讯作者：
Maines, Mahin D.
中科院分区：
文献类型：
--
作者：
Gibbs, Peter E. M.;Maines, Mahin D.
HBVR在细胞中的作用是作为一种还原酶和一种激酶。在第一种能力中，它将HO活性的产物胆绿素还原为有效的细胞内抗氧化剂胆红素；作为一种双特异性激酶(S/T/Y)，它激活MAPK和IGFIRK受体信号转导通路。核因子-kappaB和MAPK通路被ROS激活，从而导致包括HO-1在内的应激诱导基因的激活。目前，我们报道了胆绿素对核因子-kappaB激活的负性作用和hBVR的反作用。胆绿素以浓度和时间依赖的方式抑制HEK293A细胞中核因子-kappa B的转录活性。在电子迁移率变化分析中，胆绿素处理的细胞的核提取物显示核因子-kappa B的DNA结合减少，而经肿瘤坏死因子-α处理的细胞的核提取物显示出更强的结合。免疫共沉淀数据显示hBVR与核因子-kappaB的65 kDa亚基结合，这依赖于肿瘤坏死因子-α的激活。HBVR的过表达增强了核因子-kappa B的基础激活和肿瘤坏死因子-α介导的激活，以及核因子-kappa B激活的iNOS基因的激活。HBVR过表达使细胞周期停滞于G(1)/G(0)期，减少S期细胞数。MCF-7细胞也观察到了类似的结果。由于细胞内核因子-kappaB活性的Janus性质和胆绿素的抑制作用，本研究结果为通过阻止胆绿素减少而获得的炎症性疾病和癌症的治疗干预提供了基础。另一方面，通过增加BVR水平，可以增强核因子-kappaB的有益功能。(C)2007年Wiley-Liss，Inc.
hBVR functions in the cell as a reductase and as a kinase. In the first capacity, it reduces biliverdin, the product of HO activity, to the effective intracellular antioxidant, bilirubin; as a dual-specificity kinase (S/T/Y) it activates the MAPK and IGF/IRK receptor signal transduction pathways. NF-kappa B and the MAPK pathway are activated by ROS, which results in the activation of stress-inducible genes, including ho-1. Presently, we report on the negative effect of biliverdin on NF-kappa B activation and the converse effect of hBVR. Biliverdin, in a concentration- and time-dependent manner, inhibited transcriptional activity of NF-kappa B in HEK293A cells. Nuclear extracts from biliverdin-treated cells show reduced DNA binding of NF-kappa B in an electromobility shift assay, whereas extracts from cells treated with TNF-alpha showed enhanced binding. Coimmunoprecipitation data show hBVR binds to the 65 kDa subunit of NF-kappa B, and that this is dependent on activation by TNF-alpha. Overexpression of hBVR enhanced both the basal and TNF-alpha-mediated activation of NF-kappa B and also that of the NF-kappa B-activated iNOS gene. Also, overexpression of hBVR arrested the cell cycle in the G(1)/G(0) phase and reduced the number of cells in S phase. Similar results were observed with MCF-7 cells. Because of the Janus nature of NF-kappa B activity in the cell and the inhibitory action of biliverdin, the present findings provide a foundation for therapeutic intervention in inflammatory diseases and cancer that may be attained by preventing reduction of biliverdin. On the other hand, by increasing BVR levels beneficial functions of NF-kappa B might be augmented. (C) 2007 Wiley-Liss, Inc.